Compounds and Compositions as Protein Kinase Inhibitors

• US 20080300267A1
• Filed: 05/15/2006
• Published: 12/04/2008
• Est. Priority Date: 05/16/2005
• Status: Abandoned Application

• Current Assignee: Toyoda Gosei Company Limited (Toyota Motor Corporation)
• Original Assignee: Toyoda Gosei Company Limited (Toyota Motor Corporation)
• Inventors: Ren, Pingda, Okram, Barun, Gray, Nathanael S.
• Application Number:
  US11/914,210
• Publication Number:
  US 20080300267A1
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/16 for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR kinases.

Claims

1. A compound selected from Formula Ia, Ib and Ic:

2. The compound of claim 1 in which:

n is selected from 0 and 1;

R₁ is C_1-6alkoxy;

R₂ is selected from C_6-10aryl-C_0-4alkyl and C_5-10heteroaryl-C_0-4alkyl;

wherein said aryl or heteroaryl of R₂ is optionally substituted by 1-3 radicals independently selected from halo, C_1-6alkyl, C_1-6alkoxy, halo-substituted-C_1-6alkyl, —

S(O)_0-2R₅, —

COOR₅, and —

NR₅C(O)R₆;

wherein R₅ is selected from hydrogen and C_1-6alkyl; and

R₆ is C_6-10aryl optionally substituted with 1 to 3 radicals independently selected from halo-substituted-C_1-6alkyl.

3. The compound of claim 2 in which:

R₁ is methoxy;

R₂ is selected from phenyl, benzyl and pyridinyl;

wherein said phenyl, benzyl or pyridinyl of R₂ is optionally substituted with 1 to 2 radicals independently selected from chloro, bromo, fluoro, methyl, trifluoromethoxy, trifluoromethyl, —

COO₂R₅, —

S(O)₂R₅ and —

NHC(O)R₆;

wherein R₅ is selected from methyl and ethyl; and

R₆ is phenyl optionally substituted with trifluoromethyl.

4. The compound of claim 1 selected from (3-Chloro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(4-Fluoro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-(4-trifluoromethoxy-phenyl)-amine;

[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;

(3,4-Difluoro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-amine;

4-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzoic acid ethyl ester;

(3-Methoxy-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3-Fluoro-benzyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3,5-Dimethoxy-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(2-Methyl-pyridin-4-yl)-[4-(H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(2-Chloro-pyridin-4-yl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(2-Methoxy-pyridin-4-yl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(4-Methanesulfonyl-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

Pyridin-4-yl-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(4-Methyl-pyrimidin-2-yl)-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3-Bromo-phenyl)-[4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3-Chloro-phenyl)-[4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

[4-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;

(3-Bromo-4-methyl-phenyl)-[4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

2-{4-[2-(3-Bromo-phenylamino)-pyrimidin-4-yl]-pyrrolo[2,3-b]pyridin-1-yl}-ethanol;

2-{4-[2-(3-Trifluoromethyl-phenylamino)-pyrimidin-4-yl]-pyrrolo[2,3-b]pyridin-1-yl}-ethanol;

2-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyrrolo[2,3-b]pyridin-1-yl}-ethanol;

2-{4-[2-(3-Bromo-4-methyl-phenylamino)-pyrimidin-4-yl]-pyrrolo[2,3-b]pyridin-1-yl}-ethanol;

{4-[1-(2-Amino-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrimidin-2-yl}-(3-bromo-phenyl)-amine;

{4-[1-(2-Amino-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrimidin-2-yl}-(3-bromo-phenyl)-methyl-amine;

{4-[1-(2-Amino-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrimidin-2-yl}-(4-trifluoromethyl-phenyl)-amine;

N-{4-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide;

[4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-amine;

(3,5-Dimethoxy-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

(3,5-Difluoro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

(3-Bromo-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

(3-Methoxy-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

(4-Chloro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

4-[4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-ylamino]-benzoic acid ethyl ester;

N-{4-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide;

(3-Chloro-phenyl)-[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

[4-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;

(3-Bromo-phenyl)-[4-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine;

N-{4-Methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-ylamino]-phenyl}-3-trifluoromethyl-benzamide;

N-Ethyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

N-(2-Methoxy-ethyl)-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

N-(3-Methoxy-propyl)-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

N-(3-Methoxy-propyl)-4-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

(3-Bromo-phenyl)-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3-Chloro-phenyl)-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

[4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;

N-(2-Methoxy-ethyl)-4-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

N-(3-Methoxy-propyl)-4-[4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-2-ylamino]-benzenesulfonamide;

(3-Bromo-phenyl)-[4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

(3-Chloro-phenyl)-[4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-2-yl]-amine;

[4-(1H-Pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;

(3-Chloro-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yl]-amine;

(3-Bromo-phenyl)-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yl]-amine; and

[4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

6. A method for treating a disease in an animal in which inhibition of kinase activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of claim 1.

7. The method of claim 6 in which the kinase is selected from CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR.

8. The use of a compound of claim 1 in the manufacture of a medicament for treating a disease in an animal in which the kinase activity of CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR contributes to the pathology and/or symptomology of the disease.